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TRβ activation confers AT2-to-AT1 cell differentiation and anti-fibrosis during lung repair via KLF2 and CEBPA

Author

Listed:
  • Xin Pan

    (Henan Normal University)

  • Lan Wang

    (Henan Normal University)

  • Juntang Yang

    (Henan Normal University)

  • Yingge Li

    (Henan Normal University)

  • Min Xu

    (Henan Normal University)

  • Chenxi Liang

    (Henan Normal University)

  • Lulu Liu

    (Henan Normal University)

  • Zhongzheng Li

    (Henan Normal University)

  • Cong Xia

    (Henan Normal University)

  • Jiaojiao Pang

    (Henan Normal University)

  • Mengyuan Wang

    (Henan Normal University)

  • Meng Li

    (Henan Normal University)

  • Saiya Guo

    (Henan Normal University)

  • Peishuo Yan

    (Henan Normal University)

  • Chen Ding

    (Fudan University)

  • Ivan O. Rosas

    (Baylor College of Medicine)

  • Guoying Yu

    (Henan Normal University)

Abstract

Aberrant repair underlies the pathogenesis of pulmonary fibrosis while effective strategies to convert fibrosis to normal regeneration are scarce. Here, we found that thyroid hormone is decreased in multiple models of lung injury but is essential for lung regeneration. Moreover, thyroid hormone receptor α (TRα) promotes cell proliferation, while TRβ fuels cell maturation in lung regeneration. Using a specific TRβ agonist, sobetirome, we demonstrate that the anti-fibrotic effects of thyroid hormone mainly rely on TRβ in mice. Cellularly, TRβ activation enhances alveolar type-2 (AT2) cell differentiation into AT1 cell and constrains AT2 cell hyperplasia. Molecularly, TRβ activation directly regulates the expression of KLF2 and CEBPA, both of which further synergistically drive the differentiation program of AT1 cells and benefit regeneration and anti-fibrosis. Our findings elucidate the modulation function of the TRβ-KLF2/CEBPA axis on AT2 cell fate and provide a potential treatment strategy to facilitate lung regeneration and anti-fibrosis.

Suggested Citation

  • Xin Pan & Lan Wang & Juntang Yang & Yingge Li & Min Xu & Chenxi Liang & Lulu Liu & Zhongzheng Li & Cong Xia & Jiaojiao Pang & Mengyuan Wang & Meng Li & Saiya Guo & Peishuo Yan & Chen Ding & Ivan O. Ro, 2024. "TRβ activation confers AT2-to-AT1 cell differentiation and anti-fibrosis during lung repair via KLF2 and CEBPA," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-52827-z
    DOI: 10.1038/s41467-024-52827-z
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